First in Human Pilot Study of Nimotuzumab with Proton Chemoradiation for Locally Advanced Head and Neck Squamous Cell Carcinoma: Acute Tolerability and Initial Clinical Response

To provide the first clinical assessment of the acute safety, feasibility, and initial efficacy of definitive intensity-modulated proton beam therapy (IMPT) combined with concurrent cisplatin and nimotuzumab for locally advanced head and neck squamous cell carcinoma (HNSCC). The combination of nimotuzumab and photon radiotherapy is established, but its safety profile with proton beam therapy (PBT) is unknown. The distinct physical (higher entrance dose) and biological (variable RBE) properties of protons could alter the toxicity and efficacy of molecular targeted agents. No prior clinical series has reported on this trimodal regimen. We retrospectively analyzed eight patients with stage III–IVA or IVC HNSCC. All received definitive IMPT (median dose 70 Gy (RBE)), with six receiving concurrent cisplatin and two (cisplatin-ineligible) receiving PBT plus nimotuzumab only. Acute toxicities (CTCAE v5.0) and 6-month tumor response (RECIST 1.1) were evaluated. The cohort (median age 49.5 years) predominantly had nasopharyngeal primaries (5/8). Acute grade ≥3 toxicities included hematologic events (5/8, 62.5%), mucositis (4/8, 50%), and dermatitis (3/8, 37.5%). No unexpected synergistic toxicity was observed. At 6 months, all eight patients (100%) achieved in-field disease control (six partial responses, one stable disease). One patient with stable local disease experienced distant progression. In this first reported cohort, the combination of IMPT, nimotuzumab, and cisplatin (where eligible) was feasible and demonstrated a manageable acute toxicity profile comparable to photon-based benchmarks. These initial safety and efficacy data support the rationale for prospective multicenter trials to validate long-term outcomes.